KR101286807B1 - Ophthalmic emulsions containing prostaglandins - Google Patents

Abstract

The present invention relates to cationic ophthalmic oil-in- water type emulsions, which comprise colloid particles having an oily core surrounded by an interfacial film, said emulsion comprising at least one cationic agent and at least one non ionic surfactant, said oily core comprising a prostaglandin selected from the group comprising in particular latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandinE<SUB>2</SUB>, or a mixture thereof, for treating ocular hypertension and/or glaucoma. These emulsions have the property to increase the chemical stability of prostaglandins.

Description

Ophthalmic emulsion containing prostaglandins {OPHTHALMIC EMULSIONS CONTAINING PROSTAGLANDINS}

The present invention relates to ophthalmic cationic underwater oil-in-water emulsions containing prostaglandins.

In the present invention, the prostaglandins used are used regardless of the prostaglandins, their precursors, or the like.

The present invention is particularly useful for prostaglandins F _2α such as latanoprost, unoprostone isopropyl, travoprost, bitotoprost, tafluprost, 8-isoprostaglandin E ₂ , or mixtures of two or more thereof.

The term ophthalmic means an emulsion that is administered to the eye and provides a pharmacological effect and is preferably applied topically. It is known to use prostaglandins in ophthalmic preparations for treating glaucoma. A problem that can arise with prostaglandins, especially latanoprost, is that the concentrations in the formulations decrease over time. U.S. Patents 011,062, 5,688,819, 5,849,792, and 4,599,353 disclose the use of several prostaglandin analogs to treat glaucoma and ocular hypertension. US Pat. No. 849,792 discloses the use of nonionic surfactants (polyethoxylated castor oil) to improve the chemical stability of prostaglandins.

However, the proposed method for improving the stability of prostaglandins is not completely satisfactory. Moreover, the use of BAK or other quaternary ammonium as a preservative for prostaglandins in ophthalmic preparations is described by C. Debbasch et al., As described in Investigative Ophthalmology & Visual Science, March 2001, Vol 42 n ° 3. Primary ammonium has been pointed out as a problem in that it has considerable toxicity in long-term use.

Like most prostaglandin analogs, latanoprost, travoprost, bimatoprost, unoprostone isopropyl, tafluprost and 8-isoprostaglandin E2 are almost insoluble in water. It is therefore interesting to provide an ophthalmic delivery means for delivering hydrophobic drugs. In recent years, oil-in-water emulsions, in particular emulsions having droplet sizes of less than 1 micron (hereinafter referred to as “submicron emulsions”), have become increasingly important, which are usually anionic emulsions. A major obstacle in developing ophthalmic drug delivery systems is the relatively low bioavailability of the drug To address this problem, cationic emulsions are being developed as topical ophthalmic delivery means. There is an advantage of increasing the bioavailability of the drug by electrostatic attraction between the negative charge and the positive charge of the emulsion, but stabilizing emulsions, including submicron emulsions, is a concern of the skilled artisan. One known method is to apply a static charge to the droplets. The repulsion of the droplets and the droplets are less coagulated.The colloidal particles dispersed in the solution are charged due to their ionic characteristics and dipolarity.These positive charges that cause negative to cationic emulsions that cause anionic emulsions (Klang) Et al., Pharm. Dev. Technology 2000, 5, 521-532), are known in the industry as “zeta potentials.” Zeta potentials are measures of interparticle repulsion or magnitude of attraction (Washington, Adv. Drug Deliv. Reviews 1996, 20 : 131-145) The following patents dealing with cationic emulsions for topical ocular administration are of particular interest.

U. S. Patent No. 6,007, 826 discloses a cationic underwater oil-in-water emulsion comprising colloidal particles with a positively charged interfacial membrane. The interfacial membranes include cationic lipids (0.05-3% by weight), such as C ₁₀ -C ₁₄ primary alkylamines (started by stearyl amines or oleyl amines), C ₁₀ -C 24 primary alkanolamines or cholesterol betainates; Phospholipid (0.5-3%) and a nonionic surfactant (0.05-3%) selected from the group consisting of poloxamer, tyloxapol, polysorbate and polyoxyethylene fatty acid esters. The concentration of oil cores is maintained in the 3-20% range. The zeta potential of the emulsions disclosed in US Pat. No. 6,007,826 is not stable to thermal stress (see Tamilvanan et al., STP Pharma Sciences 2001, 11: 421-426 and Example 12).

Thus, an ophthalmic prostaglandin product that is at least as effective as a commercial product, is chemically stable, less toxic, and more physically or chemically stable than the conventional product, that is, it is stable over time and provides good resistance to patients. This is necessary. In the present invention, the term 'lapse of time' means a duration exceeding 1 year, preferably 2 years, more preferably 3 years.

'Good resistance' in the present invention is understood that the ratio of therapeutic benefit and eye discomfort is acceptable to the patient and preferably close to a placebo or 0.9% NaCl solution.

In general, the content of cations in the formulation should not exceed 0.1%, preferably not exceed 0.05%, and more preferably not exceed 0.03% to show good resistance. Quaternary ammines, such as benzalkonium chloride, benzododecinium bromide, and benzetonium chloride, have been approved by the health authority for ophthalmic administration at concentrations of about 0.03% (Furrer et al., Eur. J. Pharm. Biopharm. 2002, 53 (263-280).

The present invention thus relates to an oil-in-water emulsion for cationic ophthalmic, the emulsion comprising colloidal particles having an oil core surrounded by an interfacial membrane, said emulsion comprising at least one cationic agent and poloxamer, At least one nonionic surfactant selected from the group consisting of tyloxapol, polysorbate, polyoxyethylene castor oil derivatives, sorbitan esters, polyoxyl stearate and mixtures of two or more thereof, wherein the oil nucleus is latano Frost, unoprostone esopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E2 or a mixture selected from the group consisting of two or more thereof, the emulsion comprising a polyvinyl compound, a water-soluble cellulose Comprising a water-soluble polymer selected from compounds and polysaccharides No.

In a preferred embodiment, the emulsions of the invention are only as drug or in combination with one or more prostaglandins selected from the group consisting of unoprostane isopropyl, traboprost, bimatoprost, tafluprost and 8-isoprostaglandin E2. It contains tanofrost.

According to a preferred embodiment, the emulsion of the invention comprises (1) polyvinyl compounds such as polyvinyl alcohol and polyvinylpyrrolidone (2) methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and / or sodium cellulose Water-soluble cellulose compounds such as and water-soluble polymers selected from (3) polysaccharides selected from alginic acid, xanthan gum, carrageenan, and chitosan. According to one embodiment, the emulsion comprises polyoxyethylene castor oil derivatives, in particular polyethoxylate castor oil, such as, for example, PEG PEG-30 PEG-35 PEG-50 castor oil.

According to another embodiment, the present emulsion does not include any polyoxyethylene castor oil derivatives.

The term “free of” in combination with a compound or compound list means that the emulsion does not include any compound of that kind.

According to certain embodiments of the present invention, the emulsion may further comprise an anti-inflammatory compound, preferably a nonsteroidal anti-inflammatory compound or an omega-3 fatty acid. Anti-inflammatory agents include COX-2 inhibitors, salicylates, 2-arylpropionic acids, N-arylanthranilic acids, oxycams, sulfonanilides, pyrazolidine derivatives, arylalkanoic acids, 3-benzolphenylracetic acids And derivatives; And cortisone, hydrocortisone, prednisone, prednisolone, methylprednisone, fluorometallon, medridone, betamethasone, loteprednol, flumethasone, mometasone, testosterone, methyltestosterone, danazol, beclomethasone, It may be selected from the group comprising steroids such as dexamethasone, dexamethasone palmitate, tramcinolone, triamcinolone, acetonide, fluorocinolone, fluorocinolone acetonide, difluprenate, limexolone and the like.

In the emulsions of the present invention, the chemical stability of prostaglandins is improved. Without being bound by any theory, it is less available to contact with chemicals that improve degradation because prostaglandins dissolve in the oil nucleus of the present emulsion. The stability is defined as the extent to which the article retains within certain limits and during storage and use (ie shelf life) and is a property of manufacture. The purpose of stability testing is to determine how the quality of a drug substance or drug product varies over time under the influence of various environmental factors such as temperature, humidity, and light, and how the recommended storage conditions, retest periods, and storage periods can be established. To provide evidence.

Although real-time stability studies include the evaluation of such factors that ultimately affect the shelf life of drugs, this is time consuming and costly. Conventionally, fast stability studies are used to predict shelf life of drugs. This fast stability study places the system for six months at a temperature of 40 ° C.

In order to understand the inherent stability mechanism of the molecule and thus to adjust the analytical procedure to be used by establishing the degradation pathway and by identifying the appropriate degradation product, Applicants have conducted stress stability tests where the emulsion is subjected to extreme conditions of a temperature of 80 ° C. for a specific time period. Developed.

The amount of prostaglandin in the oil nucleus of the emulsion according to the invention depends on the nature of the prostaglandin and its intended use. According to one embodiment, the amount of the drug selected from the group comprising or consisting of latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E2, or a mixture of two or more is 0.001 % To 1% w / w, preferably 0.002% to 0.3% w / w and more preferably 0.004% to 0.15% w / w.

In the present application, percentages are expressed as weight (% w / w) relative to the total weight of the emulsion. The concentration of the cationic agent is from 0.001 to 0.1% w / w, preferably from 0.002 to 0.05% w / w and more preferably from 0.003 to 0.03% w / w.

The concentration of the oil core is 7% w / w or less, preferably 0.5 to 5% w / w and more preferably 1 to 3% w / w.

The concentration of the nonionic agent is 1% w / w or less, preferably 0.01 to 0.6% w / w.

The cationic agent is a C ₁₀ -C ₂₄ primary alkylamine, tertiary aliphatic amine, benzalkonium halide, lauralconium halide, cerimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide , Cetrimonium halides, benzetonium halides, behenalconium halides, cetalconium halides, cetetyldimonium halides, cetylpyridium halides, benzododecinium halides, chloralyl methammine halides, myritalconium halides, stearals Quaternary ammonium compounds selected from the group consisting of cornium halides or mixtures of two or more, wherein the halides are halides, preferably chloride or bromide-cationic lipids, amino alcohols, chlorohexidine and salts thereof, polyaminopropyl biguan , Phenformin, alkylbiguanides or mixtures of two or more Biguanide salts selected from the group consisting or consisting of: 1, 2-dioleyl-3-trimethylammonium-propane, 1,2-dioleoyl-sn-glycero-phosphatidylethanolamin, cationic glycospingo- And a cationic compound selected from lipids or cationic cholesterol derivatives or mixtures of two or more thereof.

According to certain embodiments of the present invention, the present emulsion does not include clohexidine and its salts. According to one preferred embodiment, the cationic agent is benzalkonium chloride, lauralconium chloride, benzododecinium bromide, benzethenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide or two or more Selected from the group comprising the mixture. According to a preferred embodiment, the cationic agent included in the emulsion of the present invention is selected from at least one quaternary ammonium halide in which the nitrogen atom is substituted with at least one alkyl group having at least 14 carbon atoms. According to a particular embodiment of the invention, the emulsion comprises benzalkonium halide as the only cationic agent.

The oil phase of this emulsion is vegetable oil (ie soybean oil, olive oil, sesame oil, cottonseed oil, castor oil, sweet almond oil), mineral oil (ie petroleum jelly and paraffin), medium chain triglycerides (MCT) (ie carbohydrate) The chain comprises triglycerides having about 8-12 carbon atoms), oil fatty acids, isopropyl myristate, oil fatty alcohols, sorbitol and esters of fatty acids, oil sucrose esters, and physiologically resistant, usually any oily substance or It may include one or more components selected from the group consisting of.

According to one embodiment of the invention, the oil phase has an iodine value of 50 or less, preferably 15 or less, more preferably 5 or less, most preferably 1 or less.

In this embodiment, the oil phase is, for example, mineral oils such as petrolatum and liquid paraffin, and light mineral oils, medium chain triglycerides (MCTs) in which carbohydrate chains are generally defined as triglyceride oils having about 8-12 carbon atoms, Coconut oil; Hardened oil including hardened cottonseed oil, hardened palm oil, hardened castor oil or hardened soybean oil; At least one component selected from the group comprising or consisting of polyoxyethylene cured castor oil derivatives including poloxyl-40 cured cast oil, polyoxyl-60 cured cast oil or polyoxyl-100 cured cast oil.

According to one preferred embodiment of the present invention, the main component on the oil is preferably any vegetable oil and / or MCT having an iodine value of 50 or less. Fatty acids or fatty alcohols may be included when the hydrophobic material to be delivered by the emulsion is not sufficiently soluble in the oil phase.

Examples of MCT oils that can be used in the emulsions of the invention are TCMTM (Societe des Oleagineux, France), Miglyol 812 ™ (Dynamit Novel, Sweden) and the like.

The nonionic surfactant is selected from the group comprising or consisting of poloxamer, tyloxapol, polysorbate, polyoxyethylene castor oil derivatives, sorbitan esters, polyoxyl stearate, and mixtures of two or more.

According to another preferred embodiment of the invention, the cationic ophthalmic emulsion comprises benzalkonium as the cationic agent and thyroxapol as the nonionic surfactant. According to another preferred embodiment of the present invention, the emulsion comprises a compound of benzoxapol and poloxamer as benzalkonium as a cationic agent and a nonionic surfactant.

The emulsion may also include antioxidants such as vitamin E, istonic agents, buffering agents, preservatives and the like.

According to one embodiment of the invention, the emulsion comprises at least one preservative. According to another embodiment of the present invention, the emulsion does not contain any preservatives.

The colloidal particles of the emulsion according to the invention have an average particle size of 1 μm or less, advantageously 300 nm or less, more advantageously 100 to 250 nm.

Emulsions of the present invention may be conditioned in a monodoses vessel or a multidoses vessel. According to one embodiment, the container for delivering the emulsion of the present invention is formed of glass, plastic material, resin, or the like.

According to another embodiment of the invention, the cationic ophthalmic emulsion may further comprise a medicinal active material in the water soluble portion of the oil nucleus or emulsion. The therapeutically active substance is a beta blocker such as levobunol, belfol, methipranolol, forskolin, cartrolol, timolol; Inhibitors of carbonic anhydrase such as brinsolamide, dorzolamide, acetazolamide, metazolamide, dichlorophenamide; Sympathetic neurostimulating agents such as brimonidine, apraclonidine, dipypirine, and epinephrine; Parasympathetic stimulants such as pilocarpine; Cholinesterase inhibitors such as physostigmine, ecothioate and / or derivatives thereof; And / or an anti-glaucoma active substance which may be selected from the group comprising optically acceptable salts thereof.

The emulsion according to the invention is physically stable over time as defined above and maintains a positive zeta potential at certain measurement conditions as described in Tests A, B, C and / or D.

In accordance with the present invention the emulsion does not contain any substance in sufficient quantity that is likely to affect zeta potential over time. Advantageously the emulsion of the invention does not comprise phospholipids. Materials that are likely to affect the zeta potential can be any material in which phospholipids and storage are charged with negative charges.

The amount of material that affects the zeta potential over time should be such that the amount of positive charge at any time is greater than the amount of negative charge.

Zeta potential

Zeta potential measures the physical characteristics exhibited by any particle in the suspension. Zeta potential can be used to optimize suspension and suspension formulations, as well as predict suspension behavior in different environments and predict stability over time. It is necessary to impart repulsion to the particles so that the emulsion droplets do not stick together and form aggregates of increasing size. One of the means of giving repulsive force in the colloidal system is by static or charge stabilization. Static or charge stabilization has the advantage of stabilizing the system by simply changing the concentration of ions in the system. This method is reversible and inexpensive.

Depending on the nature of the particle and the medium surrounding it, there may be many origins of surface charge, but the most important mechanism is the ionization of surface groups or the adsorption of charged ions.

The interaction of particles in polar solutions is not governed by the potential at the particle surface, but by the effective potential of the particles and their associated ions. It is the zeta potential of the particles that must be measured rather than the surface charge to take advantage of the electrostatic control of dispersion. The charged particles will attract ions of opposite charge in the dispersant. The ions near the surface bind strongly, forming more diffusion regions further away. An imaginary boundary, known as the sleeping surface, falls within this range, and within this range the particles and ions act as a monolith.

The potential at the sleeping surface is known as the zeta potential. It is long known that zeta potential is a very good indicator of the strength of interaction between colloidal particles and the measurement of zeta potential is usually used to evaluate the stability of colloidal systems. The zeta potential measured within a particular system depends on the surface chemistry and also on the chemistry of the way it interacts with the environment. The zeta potential should therefore always be studied in a well defined environment (specifically pH and ionic strength).

Electric mobility

An important consequence of the presence of charges on the surface of the particles is that they interact by the applied electric field. These effects are collectively defined as interfacial galvanic effects. If movement is induced in a particle suspended in a liquid under the influence of an applied electric field, it is more specifically named electrophoresis. When an electric field is applied to the electrolyte, conductive particles suspended in the electrolyte are attracted toward the electrode of opposite charge. Viscous forces acting on the particles tend to retard this movement. When equilibrium is reached between these two forces, the particles move at a constant speed. The speed depends on the strength or voltage gradient of the electric field, the dielectric constant of the medium, the viscosity of the medium and the zeta potential. The velocity of particles in a unit electric field is called the electrical mobility. Zeta potential is related to electrical mobility by the Henry equation.

 Where UE = electrical mobility, z = zeta potential, ε = dielectric constant, η = viscosity, and f (Ka) = Henry's function.

Electrophoretic analysis of zeta potential is generally carried out in an aqueous medium and at an appropriate electrolyte concentration. In this case f (Ka) is 1.5 and this is called Smolukowski approximation. The calculation of the zeta potential in mobility is thus direct for particles larger than approximately 0.2 dispersed in a system suitable for the Smolukowski model, ie, electrolytes containing at least 10-3 molar salts. In low dielectric constant media (such as non-aqueous media) it is 1.0 for less particles and allows the same simple calculation. This is called the Hukel approximation.

Test A, B, C and D

Test A is a measure of the stability of the emulsion zeta potential under thermal stress.

The zeta potential of the emulsion is measured immediately after T = 0, ie the emulsion is prepared, and the value obtained is called Z0. An effective volume of 10 ml glass bottle (type I) containing 5-10 ml of the emulsion and sealed (without bubbles) under nitrogen gas is stored at 80 ° C.

The zeta potential (Z15h) is then measured at T = 15 hours. The value δA = Z _15h -Zo is then calculated. For each measurement of the zeta potential, it is calculated as follows.

The zeta potential of the emulsion droplet surface is measured by electrical mobility in a device such as Malvern Zetasizer 2000 (Malvern Instruments, UK), which is calibrated to the supplied standard with suitable software.

The emulsion is diluted with distilled water twice as needed to obtain scattering strength which allows for optimal particle search. The count rate of the sample should be within 100 to 1000 KCps for homodyne search (subtract the contribution of the reference beam if using heterodyne search). Three consecutive measurements are performed at 2525 ° C using a constant cell drive of 150mV. The electrical mobility is converted to the zeta potential value using the Smolukowski equation using the dielectric constant and the viscosity of the water. The measured value corresponds to the average of three obtained values.

If δ A is below the standard error of the measurement, preferably 10 mV or less, more preferably 5 mV or less, the emulsion is considered to meet the zeta potential stability test A. According to an advantageous embodiment, the ophthalmic emulsion according to the invention meets the zeta potential stability test B.

Test B is the same as Test A except that the emulsion is stored at 80 ° C. for 48 hours, the zeta potential Z ₂ is measured on day _{2 and} δ B = Z ₂ -Zo is calculated. If δB is below the standard error of the measurement, preferably 10 mV or less, more preferably 5 mV or less, the emulsion is considered to meet the zeta potential stability test B. According to a more advantageous embodiment, the ophthalmic emulsion according to the invention meets the zeta potential stability test C.

Same as test A, except that the emulsion is stored at 80 ° C. for 7 days, the zeta potential Z7 is measured on day _{7, and} δC = Z ₇ -Zo is calculated. If δC is below the standard error of the measurement, preferably 10 mV or less, more preferably 5 mV or less, the emulsion is considered to meet the zeta potential stability test C.

According to an advantageous embodiment, the ophthalmic emulsion according to the invention meets the zeta potential stability test D.

Same as test A, except that the emulsion is kept at 80 ° C. for 14 days, the zeta potential Z14 is measured on day 14 and δD = Z ₁₄ -Zo is calculated. If δD is below the standard error of the measurement, preferably 10 mV or less, more preferably 5 mV or less, the emulsion is considered to meet the zeta potential stability test D.

According to another aspect, the present invention relates to a method of preparing the emulsion described above. The emulsion is prepared as follows.

Prostaglandins are dissolved in an oil phase with the addition of another hydrophobic ophthalmic active ingredient.

A water-soluble phase with the optional addition of another hydrophilic ophthalmic active ingredient is quickly added to the oil phase.

The coarse emulsion thus obtained is preferably heated rapidly to 75 ° C.

Then reduce the size of the emulsion droplets by any suitable means known in the art such as, for example, shear mixing.

The emulsion temperature is cooled to 20 ° C. using an ice bath and then homogenized.

Adjust the pH to 7-8.

Sterilize the emulsion.

The invention also relates to the use of cationic ophthalmic oil-in-water emulsions as described above for the preparation of ophthalmic compositions for treating ocular hypertension and / or for treating glaucoma.

According to another aspect, the invention relates to an ophthalmic formulation comprising an emulsion as described above in the form of eye drops, ophthalmic ointments, ophthalmic gels and the like, optionally an emulsion in combination with an ophthalmic acceptable carrier. In the ophthalmic formulations described above, there may be a pharmaceutically effective amount of the active ingredient in an ophthalmically acceptable carrier.

The present invention also relates to a delivery device selected from the group comprising a lens, eye patch, implant, insert, such delivery device comprising an emulsion as described above.

The invention is further illustrated by the following examples.

Yes

In the following examples the following abbreviations are used.

Medium chain triglycerides MCT: TCM ™ (Societe des Oleagineux)

BAK: Benzalkonium Chloride (FeF Chemicals, Denmark)

Lutrol: Rootroll F68 ™ (BASF)

Tyloxapol: Triton WR1339 (Ruger Chemicals, USA)

Z29: latanofrost

Example  One

The oily phase component, including 0.005% ratanoprost (named Z29 in the table), was magnetically wet while weighing continuously in the beaker and heating slightly (40 ° C) until a slight viscous phase was obtained. The aqueous phase component was continuously weighed in the beaker and magnetically wet with slight heating (40 ° C.) until a clear and clear flowable liquid was obtained. Both phases were heated to 65 ° C. The aqueous phase was quickly added into the oil phase to form a crude emulsion which was then quickly heated to 75 ° C. The water-soluble phase and coarse emulsion beakers were filmed to prevent evaporation of moisture. The emulsion was white and slightly transparent. The droplet size of the emulsion was then reduced by high shear mixing for 5 minutes with polytron PT6100. The emulsion turned milky white. The temperature of the emulsion was cooled to 20 ° C. using an ice bath.

The final emulsion was obtained by homogenization in a microfluidizer (C5, Avestin) using a continuous cycle of 5 mm at a pressure of 10,000 psi. The emulsion was milky white, very fluid and did not stick to the glass. The emulsion temperature was reduced to 25 ° C. The pH was measured and then adjusted to 7.0 using 0.1 M HCl or 0.1 M NaOH. The emulsion was stored in a glass bottle with nitrogen bubbles and sterilized at 121 ° C. for 20 minutes in an autoclave.

The average particle size of the emulsion droplets was measured by quasi-elastic light scattering after dilution with water using a high performance particle sizer (Malvern Instruments, UK).

Diluted 1: 200 in twice distilled water as described above and measured the electrical mobility at 25 ° C. with Malvern Zetasizer 2000 (Malvern Instruments, UK) and converted to zeta potential via Smolukowski equation.

Example   2

Improved latanofrost stability in emulsions compared to commercial products (Xalatan ^® )

The chemical stability of latanoprost in the emulsion was compared with the commercial product (Xalatan®) at 80 ° C. for 14 days (Table 1).

Prostaglandin components were analyzed by HPLC-UV method.

In the emulsions according to the invention the latanoprost is chemically stabilized.

Example  3:

Vivo studies demonstrate that latanoprost emulsions are as effective as commercially available products (Xalatan ^® ) in reducing IOP.

Methods: Eight mature female chinomolgus monkeys, 3-6 kg each, induced glaucoma by diode laser photocoagulation in a medial fibrous net were used in this study.

0 h (prior to drug administration) and one base day, one vehicle treated, and 30 μl of Z29EM007 (same as the emulsion described in Example 1) or 0.005% of latanoprost (Xalatan; Pharmarcia & Upjohn, Kalamazoo, Intraocular pressure (IOP) was measured every hour up to 6 hours after drug administration for the first, third, and fifth days treated with Ml).

The product was applied topically to the glaucoma eye once daily for five consecutive days in a crossover design with at least two weeks washout period between the two pills.

Results: By administering both Z29EM007 and Xalatan once daily for 5 days, I0P was significantly reduced (p <0.005) from 1 hour to 5 hours after the first dose compared to vehicle treatment days (Table 2).

Repeated administration of both Z29EM007 and Xalatan improved the effect of intraocular pressure. When comparing Z29EM007 and Xalatan, no statistical difference was observed for IOP reduction (p> 0.80) over 5 days of treatment. There was no statistical difference in IOP between baseline and vehicle treatment days (p> 0.90).

The latanoprost in the emulsions according to the invention is as effective as the commercial Xalatan ™.

The present invention is an ophthalmic use that is as effective as a commercial product, has the chemical stability of prostaglandins, is less toxic, physically or chemically more stable than conventional products, ie is stable over time and provides good resistance to patients. Providing prostaglandin products, using cationic ophthalmic oil-in-water emulsions for the preparation of ophthalmic compositions for treating ocular hypertension and / or treating glaucoma, and in the form of eye drops, ophthalmic ointments, ophthalmic gels, etc. An ophthalmic formulation comprising an emulsion, such as one, optionally an emulsion in combination with an ophthalmic acceptable carrier. The present invention also provides a delivery device selected from the group comprising a lens, eye patch, implant, insert, such delivery device comprising the emulsion of the invention described above.

Claims (28)

A cationic ophthalmic oil-in-water emulsion comprising colloidal particles having an oil nucleus surrounded by an interfacial membrane, the emulsion comprising at least one cationic agent and poloxamer, thyroxapol, polysorbate, polyoxyethylene cast oil derivative, sorbent At least one nonionic surfactant selected from the group consisting of inelastic esters, polyoxyl stearate, and mixtures of two or more thereof, wherein the oil nucleus is latanoprost, unoprostone isopropyl, traboprost, bimato And a drug selected from the group consisting of frost, tafluprost, 8-isoprostaglandin E ₂ or a mixture of _two or more thereof, wherein the emulsion is free of water-soluble polymers selected from polyvinyl compounds, water-soluble cellulose compounds and polysaccharides. Cationic ophthalmic oil in water Type emulsion. 2. The cationic ophthalmic oil-in-water emulsion according to claim 1, wherein the drug is latanofurst. The method of claim 1, wherein the emulsion is free of a water-soluble polymer selected from (1) a polyvinyl compound (2) a water soluble cellulose compound, and (3) a polysaccharide selected from alginic acid, xanthan gum, carrageenan, and chitosan. Underwater oil emulsion for cationic ophthalmology. The cationic ophthalmic oil-in-water emulsion of claim 1, further comprising at least one medicinal active substance. The cationic ophthalmic oil-in-water emulsion of claim 1, further comprising an anti-inflammatory compound. The method of claim 1, wherein the emulsion comprises a beta blocker; Inhibitors of carbonic anhydrase; Sympathetic nervous system; Parasympathetic nervous system; Cholinesterase inhibitors and derivatives thereof; Optically acceptable salts; And at least one anti-glaucoma medicinal active substance selected from the group comprising a combination thereof. The method of claim 1, wherein the selected from the group consisting of latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E ₂ or a mixture of _two or more in the oil nucleus. Cationic ophthalmic oil-in-water emulsion, characterized in that the amount of drug is 0.001 to 1% w / w. The cationic ophthalmic oil-in-water emulsion of claim 1, wherein the concentration of the cationic agent is 0.001 to 0.1% w / w. The cationic ophthalmic oil-in-water emulsion of claim 1, wherein the concentration of the oil core is 7% w / w or less. The cationic ophthalmic oil-in-water emulsion of claim 1, wherein the concentration of the nonionic agent is 1% w / w or less. The method of claim 1, wherein the cationic agent is composed of C10-C24 primary alkylamine, tertiary aliphatic amine, quaternary ammonium compound, cationic lipid, amino alcohol, biguanide salt, cationic compound and a mixture of two or more thereof. Cationic ophthalmic underwater oil-in-water emulsion, characterized in that selected from the group consisting of. 12. The salt of claim 11 wherein the biguanide salt is selected from the group comprising chlorhexidine and salts thereof, polyaminopropyl biguanide, phenformin, alkylbiguanide or a mixture of two or more thereof. Underwater oil emulsion for cationic ophthalmology. 12. The quaternary ammonium compound of claim 11, wherein the quaternary ammonium compound is benzalkonium halide, lauralconium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzetonium Include halides, behenalconium halides, cetalconium halides, cetetyldimonium halides, cetylpyridium halides, benzododecinium halides, chloralyl methenammine halides, myritalconium halides, stearalconium halides or mixtures of two or more Cationic ophthalmic underwater oil-in-water emulsion, characterized in that selected from the group. The method of claim 1, wherein the cationic agent is benzalkonium chloride, lauralconium chloride, benzododecinium bromide, benzethenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide or a mixture of two or more thereof. Cationic ophthalmic underwater oil-in-water emulsion, characterized in that selected from the group comprising. The cationic ophthalmic oil-in-water emulsion according to claim 1, wherein the cationic agent is selected from at least one quaternary ammonium halide in which the nitrogen atom is substituted with at least one alkyl group having at least 14 carbon atoms. The cationic ophthalmic oil-in-water emulsion of claim 1, wherein the oil phase has an iodine value of 50 or less. 17. The method of claim 16, wherein the oil phase is mineral oil, and light mineral oil, medium chain triglycerides (MCT), coconut oil; Hardened oil including hardened cottonseed oil, hardened palm oil, hardened castor oil or hardened soybean oil; A cation comprising at least one component selected from the group consisting of polyoxyethylene cured castor oil derivatives comprising poloxyl-40 cured cast oil, polyoxyl-60 cured cast oil or polyoxyl-100 cured cast oil Castle ophthalmic underwater remains emulsion. 2. The cationic ophthalmic oil-in-water emulsion of claim 1, wherein the oil is MCT. 2. The cationic ophthalmic oil-in-water emulsion of claim 1, comprising benzalkonium chloride as a cationic agent and thyroxapol as a nonionic surfactant. 2. The cationic ophthalmic oil-in-water emulsion of claim 1, wherein the emulsion comprises benzalkonium chloride as a cationic agent and a compound of thyroxapol and poloxamer. The cationic ophthalmic oil-in-water emulsion of claim 1, wherein the colloidal particles have an average particle size of 1 μm or less. The cationic ophthalmic oil-in-water emulsion of claim 1, wherein the emulsion meets the conditions of Zeta Potential Stability Test A. The cationic ophthalmic oil-in-water emulsion of claim 1, wherein the emulsion meets the conditions of Zeta Potential Stability Test B. The cationic ophthalmic oil-in-water emulsion according to claim 1, wherein the emulsion meets the conditions of Zeta potential stability test C. The cationic ophthalmic oil-in-water emulsion according to claim 1, wherein the emulsion meets the conditions of the zeta potential stability test D. 26. Cationic ophthalmic oil-in-water emulsion according to any one of claims 1 to 25 for the preparation of ocular hypertension, glaucoma or ophthalmic composition for treating them. 26. An ophthalmic formulation comprising an emulsion according to any one of claims 1 to 25, optionally in combination with an ophthalmically acceptable carrier, wherein the formulation is in the form of eye drops, ointments, ophthalmic gels. Ophthalmic formulation characterized. A delivery device selected from the group comprising a lens, eye patch, implant, insert, said delivery device comprising an emulsion according to any one of claims 1 to 25.